The overall theme of this Program Project Grant continues to be chemical and neural regulation of respiratory system activity. While continuing the same theme, the studies proposed for an additional five years focus on dynamics of long-term effects, plasticity and adaptations of the respiratory system activity to chronic intermittent hypoxia (CIH). All six projects in the renewal application examine the effects of CIH at various levels of the respiratory control system that includes the sensor, controller and the plant. The focus of the Project 17 is to define by what mechanisms intermittent hypoxia affects 02 sensing ability of the carotid body and its consequences on respiratory motor output. Projects 18 and 14 examine the effects of intermittent hypoxia on chemoafferent pathway, that includes the sensory neurons in petrosal ganglion that innervate carotid body, and neurons in nTS that integrate carotid body inputs. While Project 18 examines the role of ion channels that determine the excitability of chemoafferent neurons, Project 14 focuses on newly described role of Brain-Derived Neurotrophic Factor (BDNF) as a potential modulator of excitatory synaptic transmission in the chemoafferent pathway. Project 19 correlates changes in respiratory motor output with sympathetic nerve activity in response to CIH and examines the role of carotid body chemoreceptors in CIH-induced sympathetic excitation. Transcriptional and post-translational modifications by CIH are the focus of the Projects 16 and 20, respectively. Project 16 utilizing the transgenic animal model examines the role of recently discovered hypoxia-inducible factor-1 (HIF-1) in ventilatory alterations by CIH. Project 20, examines the effects of CIH on enzyme activities associated with transmitter synthesis in the chemoafferent neurons. Core 9007 fulfills the need to provide central facilities for exposing animals to CIH, imaging, histo- and biochemical analysis, microarray GeneChip technology for global gene expression and a Core Unit dedicated for mathematical modeling of experimental data. Recurrent episodes of hypoxia are experienced often in life and are associated with many pulmonary diseases perhaps more so than sustained hypoxia. CIH affects the ventilatory control system resulting in enhanced chemosensitivity and leads to pulmonary as well as systemic hypertension, myocardial and brain infarctions, cognitive dysfunction, and sudden death in the elderly. In view of clinical and physiological significance, it will be extremely important to understand the cellular and integrative mechanisms by which CIH affects the respiratory control system, so that appropriate interventions can be developed. The integrative and comprehensive nature of this Program offers maximal collaborative efforts and enhances the impact of knowledge that eventually emerges from this Program. Because of the tight thematic linkages across the projects, which we believe is the major strength, the total knowledge accrued from the proposed studies will truly be greater than sum of each project.